The finding could provide some reassurance after the US Food and Drug Administration (FDA) recently warned of an increased risk of cancer and heart disease associated with medications in the same class as upadacitinib.
“Serious adverse events were numerically lower in patients on upadacitinib, and discontinuations from the study due to adverse events were also lower” than in patients taking a placebo, said Edward Loftus, MD, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota.
Loftus presented the findings from the U-ACCOMPLISH study here at the American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting.
Although other medications are approved for the treatment of ulcerative colitis, including biologics, many patients do not respond. In 2019, tofacitinib (Xeljanz) became the first JAK inhibitor approved for this condition. It works by blocking the JAK-1 and JAK-3 inflammation pathways, and at high concentrations, it also blocks the tyrosine kinase 2 (TYK2) and JAK-2 pathways.
However, adverse events seen in clinical trials of tofacitinib include pneumonia, herpes zoster, anal abscess, and Clostridioides difficile infections. And, as reported by Medscape Medical News in September, the FDA required its manufacturer, Pfizer, to add a boxed warning that includes information about the risks of stroke, cancer, blood clots, and death.
Upadacitinib may be more selective and reversible because it preferentially blocks JAK-1 or JAK1/3. In August 2019, it received FDA approval at a dose of 15 mg for adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.
But the FDA applied the same warnings to upadacitinib — and to a third related drug, baricitinib (Olumiant) — that it required for tofacitinib, even though they are not as well studied.
The FDA also limited approved uses of these three medications to patients who have not responded well to tumor necrosis factor (TNF) blockers to ensure their benefits outweigh their risks.
A Well-Tolerated Treatment
U-ACCOMPLISH is one of two phase 3 trials induction trials completed on upadacitinib.
Investigators randomized 522 people with moderately to severely active ulcerative colitis, defined as Adapted Mayo Score 5-9 with a centrally read endoscopic score of 2-3. Of those patients, the intent to treat population included 341 in the upadacitinib group (45 mg once daily) and 174 in the placebo group.
The baseline demographics and disease characteristics were similar between groups. More than two thirds of patients in both groups were white, and more than two thirds were men. In the upadacitinib group, 50.7% had responded inadequately to biologic treatments, compared to 51.1% in the placebo group.
After 8 weeks, a significantly higher proportion of patients receiving upadacitinib achieved clinical remission as defined by the adapted Mayo Score (stool frequency subscore ≤1 and not greater than baseline, rectal bleeding subscore of 0, and Mayo endoscopic subscore ≤ 1).
|Table 1. Efficacy|
|Outcomes||Upadacitinib, n = 341||Placebo, n = 174||P value|
|Clinical remission (by Adapted Mayo Score), %||33.5||4.1||< .001|
|Clinical response (by Adapted Mayo Score), %||74.5||25.4||< .001|
|Endoscopic Improvement, %||44.0||8.3||< .001|
|Histologic-Endoscopic Mucosal Improvement, %||36.7||5.8||< .001|
“In terms of the efficacy, I think it’s very, very promising,” said Derrick Eichele, MD, an assistant professor of gastroenterology-hepatology at the University of Nebraska Medical Center in Omaha, who was not involved in the trial.
The efficacy data were similar to those reported for tofacitinib in clinical trials, he said. “But I think again, what we’re waiting to see is how is this going to be positioned in relation to tofacitinib in terms of safety profile,” he told Medscape Medical News.
More patients in the upadacitinib group reported adverse events, including those deemed related to the drug. However, the proportion that were severe, serious, or led to discontinuation was higher in the placebo group. No one in the study died, and no one in the upadacitinib group had an adjudicated major adverse cardiovascular event, tuberculosis, or malignancy.
|Table 2. Safety|
|Any Adverse Events, %||39.5||52.9|
|Adverse Events Possibly Related to Study Drug, %||6.8||23.5|
|Severe Adverse Events, %||4.0||2.6|
|Serious Adverse Events, %||4.5||3.2|
|Adverse Events Leading to Discontinuation, %||5.1||1.7|
The most common adverse events were acne, blood creatine phosphokinase elevation, and anemia, which were all more common in the upadacitinib group, and headache and worsening of ulcerative colitis, which were more common in the placebo group.
Among adverse events of special interest, anemia, neutropenia, hepatic disorder, lymphopenia, serious infection, and opportunistic infection were more common in the upadacitinib group than in the placebo group. The four opportunistic infections in the upadacitinib group included two cases of herpes zoster.
In reviewing the poster presented at this meeting, the cases of neutropenia and hepatic disorder in the upadacitinib group stood out for Eichele. But he said it’s hard to pass judgment based on this amount of data. He is looking forward to a peer-reviewed publication. “I’ll be interested to see what it shows in terms of the details,” he said.
Phase 3 trials of upadacitinib are underway in atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, Crohn’s disease, giant cell arteritis, and Takayasu arteritis as well as ulcerative colitis.
In a 52-week maintenance trial, according to a press release, malignancies (excluding nonmelanoma skin cancer) included one event among 148 people taking a 15-mg dose of upadacitinib 15, two events among 154 people taking a 30-mg dose of upadacitinib, and one event among 149 people in the placebo group.
Two cases of pulmonary embolism were reported in the 15-mg group and two cases of deep vein thrombosis were reported in the 30-mg group, compared to one event of ovarian vein thrombosis in the placebo group. One adjudicated major cardiovascular event each were reported in the upadacitinib 30-mg group and the placebo group. No one died.
The study was funded by AbbVie. Loftus reported that he is a consultant for AbbVie as well as multiple other gastroenterology drug companies. Eichele has disclosed no relevant financial relationships.
American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting: Abstract P0575. Presented October 24, 2021.
Laird Harrison writes about science, health, and culture. His work has appeared in national magazines, in newspapers, on public radio, and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at www.lairdharrison.com or follow him on Twitter: @LairdH.